Cortico-mesolimbic dopamine (CM-DA) function is the primary neurochemical mediator of cocaine reinforcement. Serotonin-3 (5-HT3) receptors modulate CM-DA function. Preclinical studies show that 5-HT3 antagonists decrease CM-DA receptor-mediated effects, including hyperlocomotion. 5-HT3 antagonists decrease cocaine-induced behavioral sensitization and tolerance and decrease self-administration, particularly in acute withdrawal states. In humans, ondansetron-pretreated individuals compared with controls show increased neuronal activation and right cerebral blood flow (rCBF). Taken together, it is, therefore, reasonable to hypothesize that ondansetron can be used to aid the restoration of normative dopamine (DA) function during the period of recent withdrawal from cocaine use, thereby decreasing the potential for relapse to drug taking once abstinence has been achieved. Human laboratory studies also show that ondansetron reduces preference for psychostimulants, including cocaine and amphetamine. Further, in a NIDA-funded randomized, double-blind, pilot study (N = 16 subjects/group) to detect a therapeutic signal for ondansetron (0.25, 1.0, and 4.0 mg b.i.d.) vs. placebo, we showed that ondansetron 4 mg b.i.d. was significantly more efficacious at increasing the weekly proportion of cocaine-free urine specimens. Hence, human laboratory and initial clinical data provide compelling evidence for the proposition that ondansetron is an efficacious treatment for cocaine dependence. As a proof-of-concept of our hypothesis, we propose to establish whether ondansetron can aid in reducing or ceasing cocaine use among currently using cocaine dependent individuals. We will do a randomized controlled trial in which subjects receive either ondansetron (4 mg b.i.d.) or placebo (N = 100 subjects/group * 2 groups = 200) as an adjunct to standardized weekly cognitive behavioral therapy (CBT) and Brief Behavioral Compliance Enhancement Treatment (BBCET) for 8 weeks. Our primary aims are to test two predictions of our hypothesis: 1) ondansetron will be superior to placebo at increasing the weekly proportion of cocaine-free (abstinent) days (assessed by a combination of self-reported use and urine analysis for benzoylecgonine, the major metabolite of cocaine), and 2) ondansetron will be superior to placebo at increasing the weekly mean proportion of subjects with cocainefree urines. Our secondary aim is to test whether: 1) ondansetron will be superior to placebo at decreasing cocaine craving, and these reductions in cocaine craving will be associated with decreased cocaine intake, and 2) ondansetron is superior to placebo at improving psychosocial functioning and quality of life, and specific reductions in cocaine use translate to general and measurable improvements in clinical functioning. This study supports the work of a new investigator to address NIDA's mission to develop safe and efficacious medicines for the treatment of cocaine dependence.